Monday, 20 June 2016

Lactobacillus reuteri rescuing [mouse] social behaviours: relevance to autism?

Continuing a recent 'probiotic theme' on this blog I've decided to talk a little about the study results reported by Shelly Buffington and colleagues [1] on how a "single species of gut bacteria can reverse autism-related social behavior in mice." I say 'talk about' but my conversations on this topic should be viewed in light of what others have also said about this study (see here for example) including the lead author (see here).

To summarise the findings: authors started from the idea that maternal obesity during pregnancy might have some implications for offspring in terms of their risk of "neurodevelopmental disorders including autism spectrum disorder (ASD)." It's something that has been covered before on this blog (see here) including the idea that inflammation or response to inflammation in-utero might be an important part of any risk mechanism (see here).

Conversations then progressed towards the possibility that the gut microbiome might play a role in that elevated risk of offspring autism following pregnancy obesity. To test this theory out, researchers fed female mice a high fat or 'normal diet' for 8 weeks, paired them for mating and gave all their offspring a regular diet. They studied social behaviour of offspring mice and observed that "MHFD [maternal high-fat diet] offspring had impaired sociability and showed no preference for social novelty."

To examine whether those mouse social behaviours were linked to the gut microbiome, researchers looked at the "bacterial composition and community structure in the feces" of offspring mice to ascertain any differences. They did find differences; indeed in one write-up of the study the authors note: "We found a clear difference in the microbiota of the two maternal diet groups." Could such bacterial differences account for the social differences noted between the groups? Quite possibly as Buffington et al reported that "co-housing one MRD [maternal regular diet] with three MHFD offspring was sufficient to rescue both the social behaviors and microbiota phylogenetic profile of MHFD offspring." Further, researchers transplanted the faecal microbiota from the MRD and MHFD offspring into germ-free mice providing "causal evidence that an imbalanced microbial ecology in the mice born to mothers on a high-fat diet is responsible for their social deficits."

Then came a big question: what was it about the maternal high-fat diet offspring microbiome that might be 'responsible' for the social issues observed? The answer or at least one answer: "L. reuteri [Lactobacillus reuteri] was the most drastically reduced (>9-fold) in the MHFD microbiota population, compared to the MRD microbiota." Subsequent addition of L. reuteri to the drinking water of MHFD offspring was instigated and: "Remarkably, treatment with L. reuteri significantly improved sociability and preference for social novelty in MHFD offspring."

As if all that wasn't enough researchers also looked at the old gut-brain axis and subsequently noted that: "L. reuteri treatment restores oxytocin levels, VTA [ventral tegmental area] plasticity and social behaviors." Oxytocin has something of an interesting possible connection to [some] autism (see here).

And rest.

As you can perhaps appreciate, this piece of research is fairly comprehensive both in terms of the methodologies used and also the findings in relation to maternal pregnancy obesity, offspring social behaviour, gut microbiome and the gut-brain axis. Certainly quite compelling evidence for some kind of effect including the concept of foetal programming allied to the idea of possible intervention.

Of course you'd be right to question whether the processes described in this mouse model would necessarily map on to the human experience and indeed the very heterogeneous autism spectrum characterised by [variable] issues with social affect for example. Similar questioning is asked of all animal studies trying to model the complexities of autism (see here). But added to other research where mouse modelling of autism 'deficits' has been to some degree 'changed' as the result of the addition of a particular bacterial species (see here) there is some reason for potential excitement. More so when one considers other research on the gut microbiome in relation to specific preparations potentially modifying the risk of 'neurospychiatric disorder' (see here) for example, and potentially affecting mood and/or behaviour (see here). Don't even get me started on toddler temperament being linked to the inner workings of the gut (see here) minus any hype.

But just before sales of Lactobacillus reuteri increase markedly there is further research to be done. Not least is the translation of elements of the Buffington research into studies of humans. Set within the idea that mapping exactly what kinds of wee beasties are residing in the gut is now fairly commonplace and has already stretched into autism research (see here) I would have thought that looking for the presence or absence of L. reuteri in certain groups (and sub-groups) on the autism spectrum and beyond should be fairly easy to do. If and when issues are found with this particular species, supplementing could be indicated bearing in mind some of the potential effects [2] noted already on this bacterium might already show indication in some cases of autism (see here). One might also see a way to look at this and other bacteria in conjunction with levels of oxytocin and possibly other important compounds too as part of that gut-brain axis. Given also that the Buffington study was a study of offspring of obese mice in terms of their sociability, does this also mean that kids born to overweight or obese mums are less likely to have age-appropriate social skills outside of any talk of autism?

There is still a research journey to be travelled in this area of investigation and, I might add, potentially linking various areas together including the idea that not all fats in a high-fat diet are necessarily the one and the same (see here)...

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[1] Buffington SA. et al. Microbial Reconstitution Reverses Maternal Diet Induced Social and Synaptic Deficits in Offspring. Cell.2016; 165: 1762-1775.

[2] Coccolrullo P. et al. Lactobacillus reuteri (DSM 17938) in Infants with Functional Chronic Constipation: A Double-Blind, Randomized, Placebo-Controlled Study. J Peds. 2010; 157: 598-602.

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ResearchBlogging.org Buffington, S., Di Prisco, G., Auchtung, T., Ajami, N., Petrosino, J., & Costa-Mattioli, M. (2016). Microbial Reconstitution Reverses Maternal Diet-Induced Social and Synaptic Deficits in Offspring Cell, 165 (7), 1762-1775 DOI: 10.1016/j.cell.2016.06.001